Genetic insights into the causal associations between immune cells and ovarian aging in the European population.

Objective: This study aimed to investigate the potential causal relationship between 731 immune cell traits and age at natural menopause (ANM), a measurable endpoint for ovarian aging.

Methods: Based on variant ANM data from the ReproGen Consortium, two-sample Mendelian randomization (MR) analyses were conducted in a European population to identify significant immune cell traits associated with menopausal timing using inverse variance weighting (IVW) methods as the primary strategy. The study performed additional scrutiny to test the robustness of the significant associations via weighted median and MR-Egger as complementary methods, heterogeneity and pleiotropy analyses, the Steiger test and reverse MR for testing directionality, and leave-one-out analysis for biased and dominant variants. Replication analyses were also carried out using an independent dataset for ANM from UK Biobank.

Results: After false discovery rate (FDR) correction, 10 significant immune cell traits were identified, suggesting putative causal associations with menopausal timing. Six immunophenotypes were associated with earlier ANM including CD39⁺ activated regulatory T cell (Treg) %activated Treg, NK% CD3^- lymphocyte and CD27 on four B cell types (IgD^-CD38^dim B cell, memory B cell, unswitched memory B cell, switched memory B cell). Four immunophenotypes were associated with later ANM: CD39⁺ resting Treg absolute count, HLA DR⁺ CD4⁺ %lymphocyte, CD24 on IgD^-CD38^dim memory B cell and HVEM (Herpesvirus Entry Mediator, also named as TNFRSF14) on CD4⁺ T cell. These results were validated in the replication dataset from UK Biobank. No reverse causation was found.

Conclusion: This study demonstrates a causal relationship between 10 immune cell traits and menopausal timing, thereby expanding our knowledge about reproductive aging from the perspectives of inflammaging.